To our knowledge, this study is the first network meta-analysis of adjunctive antimicrobial agents in treatment of residual pockets.
The results indicated that adjunctive local antimicrobial agents achieved a small additional treatment effect in PPD reduction and CAL gain compared with SRP alone in residual pocket for follow-up period up to six months. The most consistent advantages were attained with the use of TCF and CHC.
Further clinical trials of follow-up period for more than six months is needed to achieve a more convincing result. Properties of each adjunctive antimicrobial agent such as patient compliance, treatment time, cost-effectiveness should be taken into
consideration when we choose one particular agent to deal with residual pockets.
Appendix
Fig.1 flowchart of manuscripts screened through the review process Records identified through -! Not used in maintenance
patient
-! Not administered locally -! Not in the sites with
residual pckets -! Used in fucation sites -! Only one qualified
Fig.2 Networks of treatment comparisons for PPD reduction in short-term follow-up (≤
3 months). SRP/S=Scaling and root planing/Scaling. PDT=Photodynamic therapy.
CHX=Chlorhexidine chip. Xan-CHX=Xanthan-based chlorhexidine gel.
Fig.3 Networks of treatment comparisons for PPD reduction in medium-term follow-up (4 months ~ 6 months). MM=Minocycline microsphere.
Fig.4 Networks of treatment comparisons for PPD reduction in long-term follow-up (
> 6 months).
Fig.5 Networks of treatment comparisons for CAL gain in short-term follow-up ( ≤ 3 months).
Fig.6 Networks of treatment comparisons for CAL gain in medium-term follow-up (4 months ~ 6 months).
Fig.7 Networks of treatment comparisons for CAL gain in long-term follow-up ( > 6 months).
Fig.8 Forest plot of random effects meta-analysis evaluating the difference in PPD change in short-term follow up (≤ 3 months).
Fig.9 Forest plot of random effects meta-analysis evaluating the difference in PPD change in medium-term follow up (4 months ~ 6 months).
Fig.10 Forest plot of random effects meta-analysis evaluating the difference in PPD change in long-term follow up (> 6 months).
Fig.11 Forest plot of random effects meta-analysis evaluating the difference in CAL change in short-term follow up (≤ 3 months).
Fig.12 Forest plot of random effects meta-analysis evaluating the difference in CAL change in medium-term follow up (4 months ~ 6 months).
Fig.13 Forest plot of random effects meta-analysis evaluating the difference in CAL change in long-term follow up (> 6 months).
Fig.14 Cumulative probability of ranking evaluating the difference in PPD change in short-term follow-up (≤ 3 months).
Fig.15 Cumulative probability of ranking evaluating the difference in PPD change in medium-term follow-up (4 months ~ 6 months).
Fig.16 Cumulative probability of ranking evaluating the difference in PPD change in long-term follow-up (>6 months).
Fig.17 Cumulative probability of ranking evaluating the difference in CAL change in short-term follow-up (≤ 3 months).
Fig.18 Cumulative probability of ranking evaluating the difference in CAL change in medium-term follow-up (4 months ~ 6 months).
Fig.19 Cumulative probability of ranking evaluating the difference in CAL change in long-term follow-up (>6 months).
Fig.20 Inconsistency estimates of the network meta-analysis PD: difference in probing pocket depth change.
CAL: difference in clinical attachment level change.
Fig.21 Funnel plot of random effects meta-analysis evaluating the difference in probing pocket depth change in short-term follow up (≤ 3 months).
Fig.22 Funnel plot of random effects meta-analysis evaluating the difference in probing pocket depth change in medium-term follow up (4 months ~ 6 months).
Fig.23 Funnel plot of random effects meta-analysis evaluating the difference in probing pocket depth change in long-term follow up (> 6 months).
Fig.24 Funnel plot of random effects meta-analysis evaluating the difference in clinical attachment level change in short-term follow up (≤ 3 months).
Fig.25 Funnel plot of random effects meta-analysis evaluating the difference in clinical attachment level change in medium-term follow up (4 months ~ 6 months).
Fig.26 Funnel plot of random effects meta-analysis evaluating the difference in clinical attachment level change in long-term follow up (> 6 months).
!
PPD#reduction#
Short/term#(≤#3#months)# Medium/term#(4#~#6#months)# Long/term#(#>#7#months)#
Network meta-analysis Pairwise Meta-analysis Network meta-analysis Pairwise Meta-analysis Network meta-analysis Pairwise Meta-analysis Estimates 95% CI Estimates 95% CI Estimates 95% CI Estimates 95% CI Estimates 95% CI Estimates 95% CI SRP+PDT' v.s.' SRP' 0.44' (0.12,0.76)' 0.45' (0.06,0.83)' 0.20' (70.14,0.53)' 0.22' (0.01,0.42)' 70.13' (70.73,0.46)' 70.13' (70.72,0.45)'
SRP+TCF' v.s.' SRP' 0.57' (0.19,0.95)' 0.56' (0.29,0.82)' 0.64' (0.20,1.08)' 0.66' (0.44,0.88)' ' ' ' '
SRP+MTZ' v.s.' SRP' 0.07' (70.28,0.42)' 0.11' (70.08,0.31)' 0.26' (70.14,0.66)' 0.07' (70.17,0.32)' ' ' ' '
SRP+DOX' 'v.s.' SRP' ' 0.05' (70.42,0.52)' 0.05' (70.24,0.34)' 0.53' (70.15,1.20)' ' ' 0.10' (70.48,0.68)' 0.10' (0.07,0.13)'
SRP+MIN' v.s.' SRP' 0.12' (70.37,0.60)' 0.21' (70.06,0.48)' 0.40' (70.30,1.09)' 0.39' (70.09,0.87)' ' ' ' '
SRP+CHC' v.s.' SRP' 0.67' (0.15,1.19)' 0.70' (70.27,1.67)' 0.65' (0.21,1.10)' 0.91' (70.24,2.06)' ' ' ' '
SRP+CHG' v.s.' SRP' 0.12' (70.62,0.86)' 0.12' (70.20,0.44)' 0.14' (70.61,0.89)' 0.14' (70.21,0.49)' ' ' ' '
SRP+MIM' v.s.' SRP' ' ' ' ' 0.30' (70.54,1.14)' 0.30' (70.21,0.81)' 70.22' (70.98,0.54)' 70.22' (70.71,0.27)'
SRP+TCF' v.s.' SRP+PDT' 0.13' (70.36,0.63)' ' ' 0.45' (70.11,1.00)' ' ' ' ' ' '
SRP+MTZ' v.s.' SRP+TCF' 70.50' (70.95,70.05)' 70.51' (70.85,70.17)' 70.38' (70.92,0.16)' 70.45(70.95,0.05)' ' ' ' ' '
SRP+DOX' v.s.' SRP+TCF' ' 70.52' (71.13,0.08)' ' ' 70.12' (70.89,0.66)' ' ' ' ' ' '
SRP+MIN' v.s.' SRP+TCF' 70.46' (70.97,0.06)' 70.51' (70.81,70.22)' 70.25' (70.97,0.47)' 70.28(70.73,0.17)' ' ' ' ' '
PPD#reduction#
Short/term#(≤#3#months)# Medium/term#(4#~#6#months)# Long/term#(#>#7#months)#
Network meta-analysis Pairwise Meta-analysis Network meta-analysis Pairwise Meta-analysis Network meta-analysis Pairwise Meta-analysis Estimates 95% CI Estimates 95% CI Estimates 95% CI Estimates 95% CI Estimates 95% CI Estimates 95% CI
SRP+CHG' v.s.' SRP+TCF' 70.45' (71.28,0.38)' ' ' 70.50' (71.37,0.37)' ' ' ' ' ' '
SRP+MIM' v.s.' SRP+TCF' ' ' ' ' 70.34' (71.29,0.60)' ' ' ' ' ' '
SRP+DOX' v.s.' SRP+MTZ' ' 70.02' (70.61,0.57)' ' ' 0.26' (70.36,0.89)' 0.08' (0.02,0.14)' ' ' ' '
SRP+MIN' v.s.' SRP+MTZ' ' 0.05' (70.47,0.56)' 70.01' (70.32,0.30)' 0.13' (70.59,0.85)' 0.17' (70.32,0.67)' ' ' ' '
SRP+CHC' v.s.' SRP+MTZ' 0.60' (70.02,1.23)' ' ' 0.39' (70.09,0.88)' 0.02' (70.05,0.09)' ' ' ' '
SRP+CHG' v.s.' SRP+MTZ' 0.05' (70.77,0.87)' ' ' 70.12' (70.97,0.73)' ' ' ' ' ' '
SRP+MIM' v.s.' SRP+MTZ' ' ' ' ' 0.04' (70.89,0.96)' ' ' ' ' ' '
SRP+MIN' v.s.' SRP+DOX' 0.06' (70.61,0.74)' ' ' 70.13' (71.05,0.79)' ' ' ' ' ' '
SRP+CHC' v.s.' SRP+DOX' 0.62' (70.08,1.33)' ' ' 0.13' (70.50,0.75)' 70.06' (70.12,0.00)' ' ' ' '
SRP+CHG' v.s.' SRP+DOX' 0.07' (70.81,0.95)' ' ' 70.39' (71.39,0.62)' ' ' ' ' ' '
Table 1. Summary of estimates and 95% CI of all pairwise comparisons in PPD reduction. Results of both traditional meta-analysis and network meta-analysis were presented. The former treatment is better than the latter one when the mean difference of PPD reduction is greater than zero. SRP = Scaling and root planing; PDT = Photodynamic therapy; TCF = Tetracycline fiber; MTZ = Metronidazole gel; DOX = Doxycycline gel; MIN = Minocycline gel; CHC = Chlorhexidine chip; CHG = Chlorhexidine gel.
CAL#gain#
Short/term#(≤#3#months)# Medium/term#(4#~#6#months)# Long/term#(#>#7#months)#
Network meta-analysis Pairwise Meta-analysis Network meta-analysis Pairwise Meta-analysis Network meta-analysis Pairwise Meta-analysis Estimates 95% CI Estimates 95% CI Estimates 95% CI Estimates 95% CI Estimates 95% CI Estimates 95% CI SRP+PDT' v.s.' SRP' 0.40' (0.17,0.63)' 0.40' (0.17,0.62)' 0.26' (70.10,0.62)' 0.25' (70.08,0.57)' 70.20' (70.88,0.49)' 70.20' (70.87,0.48)'
SRP+TCF' v.s.' SRP' 0.30' (0.05,0.54)' 0.28' (0.10,0.45)' 0.31' (70.11,0.72)' 0.29' (0.04,0.55)' ' ' ' '
SRP+MTZ' v.s.' SRP' 0.18' (70.06,0.42)' 0.19' (0.00,0.38)' 0.33' (70.08,0.74)' 0.18' (70.19,0.55)' ' ' ' '
' ' '
SRP+DOX' 'v.s.' SRP' ' 0.30' (70.03,0.63)' 0.30' (0.28,0.32)' 0.70' (0.09,1.31)' ' ' 0.20' (70.43,0.83)' 0.20' (0.15,0.25)'
SRP+MIN' ' v.s.' SRP' 0.03' (70.30,0.37)' 0.06' (70.24,0.37)' 0.18' (70.40,0.76)' 0.04' (70.32,0.39)' ' ' ' '
SRP+CHC' ' v.s.' SRP' 0.48' (0.11,0.85)' 0.61' (70.30,1.52)' 0.60' (0.18,1.02)' 0.77' (70.23,1.77)' ' ' ' '
SRP+CHG' ' v.s.' SRP' 0.02' (70.49,0.53)' 0.02' (70.37,0.41)' 0.19' (70.64,1.02)' 0.19' (70.41,0.79)' ' ' ' '
SRP+MIM' ' v.s.' SRP' ' ' ' ' 0.27' (70.52,1.06)' 0.27' (70.27,0.81)' 70.52' (71.32,0.28)' 70.52' (71.02,70.02)'
' SRP+TCF' v.s.' SRP+PDT' 70.10' (70.43,0.23)' ' ' 0.05' (70.50,0.60)' ' ' ' ' ' '
SRP+MTZ' v.s.' SRP+TCF' 70.11' (70.41,0.18)' 70.18' (70.45,0.09)' 0.02' (70.50,0.55)' 70.15(70.65,0.35)' ' ' ' ' '
SRP+DOX' v.s.' SRP+TCF' ' 0.00' (70.41,0.42)' ' ' 0.39' (70.31,1.10)' ' ' ' ' ' '
SRP+MIN' v.s.' SRP+TCF' 70.26' (70.61,0.09)' 70.30' (70.59,70.02)' 70.13' (70.73,0.48)' 70.11(70.46,0.23)' ' ' ' ' '
CAL#gain#
Short/term#(≤#3#months)# Medium/term#(4#~#6#months)# Long/term#(#>#7#months)#
Network meta-analysis Pairwise Meta-analysis Network meta-analysis Pairwise Meta-analysis Network meta-analysis Pairwise Meta-analysis Estimates 95% CI Estimates 95% CI Estimates 95% CI Estimates 95% CI Estimates 95% CI Estimates 95% CI
SRP+CHC' v.s.' SRP+TCF' 0.18' (70.25,0.62)' ' ' 0.30' (70.27,0.86)' ' ' ' ' ' '
SRP+CHG' v.s.' SRP+TCF' 70.28' (70.84,0.29)' ' ' 70.12' (71.04,0.81)' ' ' ' ' ' '
SRP+MIM' v.s.' SRP+TCF' ' ' ' ' 70.04' (70.93,0.85)' ' ' ' ' ' '
SRP+DOX' v.s.' SRP+MTZ' ' 0.12' (70.29,0.53)' ' ' 0.37' (70.18,0.92)' 0.30' (0.24,0.36)' ' ' ' '
SRP+MIN' v.s.' SRP+MTZ' ' 70.15' (70.51,0.22)' 70.12' (70.44,0.19)' 70.15' (70.78,0.48)' 0.03' (70.44,0.50)' ' ' ' '
SRP+CHC' v.s.' SRP+MTZ' 0.30' (70.14,0.73)' ' ' 0.27' (70.18,0.72)' 0.13' (0.05,0.21)' ' ' ' '
SRP+CHG' v.s.' SRP+MTZ' 70.16' (70.73,0.40)' ' ' 70.14' (71.07,0.78)' ' ' ' ' ' '
SRP+MIM' v.s.' SRP+MTZ' ' ' ' ' 70.06' (70.95,0.83)' ' ' ' ' ' '
SRP+MIN' v.s.' SRP+DOX' 70.27' (70.74,0.21)' ' ' 70.52' (71.31,0.27)' ' ' ' ' ' '
SRP+CHC' v.s.' SRP+DOX' 0.18' (70.31,0.67)' ' ' 70.10' (70.65,0.45)' 70.17' (70.24,70.10)' ' ' ' '
SRP+CHG' v.s.' SRP+DOX' 70.28' (70.89,0.33)' ' ' 70.51' (71.54,0.52)' ' ' ' ' ' '
Table 2. Summary of estimates and 95% CI of all pairwise comparisons in CAL gain. Results of both traditional meta-analysis and
greater than zero. SRP = Scaling and root planing; PDT = Photodynamic therapy; TCF = Tetracycline fiber; MTZ = Metronidazole gel; DOX = Doxycycline gel; MIN = Minocycline gel; CHC = Chlorhexidine chip; CHG = Chlorhexidine gel.
Table 3: Summary of all pairwise comparisons in terms of PPD reduction and CAL gain in short-term follow-up. The upper/left-most comparison of each comparison is the reference treatment. SRP/S = Scaling and root planing/Scaling
Table 4: Summary of all pairwise comparisons in terms of PPD reduction and CAL gain in medium-term follow-up. The upper/left-most comparison of each comparison is the reference treatment. SRP/S = Scaling and root planing/Scaling.
Table 5: Summary of all pairwise comparisons in terms of PPD reduction and CAL gain in long-term follow-up. The upper/left-most comparison of each comparison is the reference treatment. SRP/S = Scaling and root planing/Scaling.
Study.# Treatment#Group# Study#Design# Periodontal#
Scaling + placebo Parallel design Ch. P./ under SPT for ≥ 3 months
Scaling + placebo Parallel design Ch. P./ under SPT for ≥ 3 months
Campos et al 2013 SRP alone Split-mouth design Ch. P./ under SPT for ≥ 3 months
13 13 1.14 1.53 0.51 0.76 3m
Campos et al 2013 SRP + PDT Split-mouth design Ch. P./ under SPT for ≥ 3 months
13 13 2.17 0.91 1.43 1.61 3m
Carvalho et al 2015 SRP + placebo Parallel design Ch. P./ under SPT 19 19 1.48 0.75 1.09 1.42 3m
Killeen et al 2016 SRP + MM Parallel design Mod. Sev. P.
Tonetti et al 2012 Scaling alone Parallel design Mod. Sev. P.
under SPT for ≥ 6
Heasman et al 2001 SRP alone Split-mouth design Mod. Sev. P.
Matesanz et al 2013 SRP + Placebo Parallel design Ch. P./ under SPT for ≥1 year
12 12 0.17 0.38 0.14 0.45 3m
Matesanz et al 2013 SRP + CHX gel Parallel design Ch. P./ under SPT for ≥1 year
10 10 0.29 0.38 0.16 0.47 3m
Matesanz et al 2013 SRP + Placebo Parallel design Ch. P./ under SPT for ≥1 year
Giannopoulou et al 2012 SRP alone Split-mouth design Ch. P./ under SPT for 3~24 months
32 29 1.9 1.054 N/A N/A 6m
Giannopoulou et al 2012 SRP + PDT Split-mouth design Ch. P./ under SPT
Kinane et al 1999 SRP + Tetra fiber Parallel design Ch. P./ under SPT
Radvar et al 1996 SRP + Metro gel Parallel design Ch. P./ under SPT for ≥ 6 months
14 14 0.95 0.60 0.57 0.56 6w
Rudhart et al 1998 SRP alone Split-mouth design Ch. P./ under SPT 46 46 1.5 0.9 0.2 1.4 13w
Rudhart et al 1998 SRP + Metro gel Split-mouth design Ch. P./ under SPT 46 46 1.7 1.2 0.4 1.3 13w
Rudhart et al 1998 SRP alone Split-mouth design Ch. P./ under SPT 46 46 1.6 0.9 0.5 1.9 25w
Rudhart et al 1998 SRP + Metro gel Split-mouth design Ch. P./ under SPT 46 46 1.6 1.0 0.7 2.2 25w
Wong et al 1998 SRP alonm Split-mouth design Ch. P./ under SPT 30 30 0.71 1.26 0.47 1.78 3m
Wong et al 1998 SRP + Tetra fiber Split-mouth design Ch. P./ under SPT 30 30 1.44 1.37 0.78 1.80 3m
Wong et al 1998 SRP alone Split-mouth design Ch. P./ under SPT 30 30 0.92 1.01 0.75 1.72 6m
Wong et al 1998 SRP + Tetra fiber Split-mouth design Ch. P./ under SPT 30 30 1.38 1.20 0.79 1.47 6m
Goh et al 2017 SRP alone Split-mouth design Ch. P./ under SPT 27 27 0.17 0.14 0.24 0.21 3m
Goh et al 2017 SRP + PDT Split-mouth design Ch. P./ under SPT 27 27 0.77 0.17 0.65 0.25 3m
Goh et al 2017 SRP alone Split-mouth design Ch. P./ under SPT 27 27 0.56 0.15 0.60 0.22 6m
Goh et al 2017 SRP + PDT Split-mouth design Ch. P./ under SPT 27 27 0.82 0.18 0.65 0.25 6m
Table 6. Characteristics of studies included in the network meta-analysis
P.,periodontitis Ch.,chronic Sev.,severe Mod.,moderate SRP,scaling and root planing NA,not available AZM,Azithromycin Doxy,Doxycycline Mino,Minocycline micro, microsphere Metro,Metronidazole CHX,Chlorhexidine
Study.# Reason#
(Dannewitz et al., 2009) Focused in furcation sites (Iwasaki et al., 2016) Not administered locally (McColl et al., 2006) Monotherapy
(Nakajima et al., 2016) Not administered locally (Nguyen et al., 2015) Not an antimicrobial agent (Ratka-Kruger et al., 2012) Monotherapy
(Slot et al., 2012) Not an antimicrobial agent (Tomasi et al., 2006) Monotherapy
(Wennstrom et al., 2011) Monotherapy
(Bardet et al., 1999) Not an antimicrobial agent (Cappuyns et al., 2012) Monotherapy
(Feng et al., 2011) Not an antimicrobial agent (Krohn-Dale et al., 2012) Monotherapy
(Lu and Chei, 2005) Insufficient data (Mongardini et al., 2014) Monotherapy
(Muller et al., 2014) Not an antimicrobial agent (Paraskevas et al., 2004) Not used only in residual pockets (Rosling et al., 2001) Not a RCT
(Ruhling et al., 2010) Monotherapy
(Serino et al., 2001) Not administered locally
(da Cruz Andrade et al., 2017) Monotherapy
(Boyd et al., 1989) Not administered locally (Brand et al., 2013) Not administered locally (Zhao et al., 2015) Not an antimicrobial agent (Cosyn et al., 2013) Not an antimicrobial agent (Escribano et al., 2010) Not administered locally (Flemmig et al., 1996) Insufficient data
(Flemmig et al., 1995) Not an antimicrobial agent (Furuichi et al., 1999) Not an antimicrobial agent (Garrett et al., 2000) Monotherapy
(Giedrys-Leeper et al., 1985) Not administered locally (Howshigan et al., 2015) Not an antimicrobial agent (Jansson et al., 2003) Insufficient data
(Jolkovsky et al., 1990) Not administered locally (Kargas et al., 2015) Not an antimicrobial agent (Kocher et al., 2005) Not an antimicrobial agent (Magnusson et al., 1989) No control group
(Magnusson et al., 1994) Not administered locally (Maze et al., 1995) Monotherapy
(Meinberg et al., 2002) Not used in maintenance phase (Nakajima et al., 2012) Not administered locally (Needleman and Watts, 1989) Focused in furcation sites (Newman et al., 1994a) Not administered locally
(Rodrigues et al., 2007) Monotherapy
(Rosling et al., 1997) Not an antimicrobial agent (Santos et al., 2004) Not used only in residual pockets (Schlagenhauf et al., 1990) Not used in maintenance phase (Soskolne et al., 2003) Not used in maintenance phase (Stabholz et al., 1991) Monotherapy
(Vandekerckhove et al., 1997a) No control group (Corsair, 1994) No control group
(Sastravaha et al., 2005) Not an antimicrobial agent (Hu et al., 2015) Monotherapy
(Khatiblou, 1994) No control group (Cattabriga et al., 1996) Not a RCT (Hagi et al., 2013) Monotherapy (Eickholz et al., 2005) Monotherapy (Zingale et al., 2012) Insufficient data (Tomasi et al., 2008) Involved furcation sites (Drisko et al., 1995) Not used in maintenance phase (Eickholz et al., 2002) Not used in maintenance phase (Graca et al., 1997) Not used in maintenance phase (Grisi et al., 2002) Not used in maintenance phase (Jeffcoat et al., 1998) Not used in maintenance phase (Jones et al., 1994) Not used in maintenance phase (Nakagawa et al., 1991) Not used in maintenance phase
(Timmerman et al., 1996) Not used in maintenance phase (van Steenberghe et al., 1999) Not used in maintenance phase (Wennstrom et al., 2001) Not used in maintenance phase (Williams et al., 2001) Not used in maintenance phase
Table 7. Studies excluded after reviewing full-text with reasons. RCT= Randomized Controlled Clinical Trials
Study.# Random#
Giannopoulou et al 2012 Low risk Low risk Unclear Unclear Low risk Low risk Unclear
Kasaj et al 2007 Low risk Unclear Unclear Unclear Low risk Low risk Low risk
Kinane et al 1999 Unclear Unclear Unclear Unclear Low risk Low risk Unclear
Leiknes et al 2007 Unclear Unclear Unclear Unclear Low risk Low risk Unclear
Newman et al 1994 Unclear Unclear Unclear Unclear Low risk Low risk Unclear
Radvar et al 1996 Unclear Unclear Unclear Low risk Low risk Low risk Unclear
Rudhart et al 1998 Unclear Unclear Unclear Unclear Low risk Low risk Unclear
Wong et al 1998 Unclear Unclear Unclear Unclear Low risk Low risk Unclear
Goh et al 2017 Low risk Low risk Unclear Unclear Low risk Low risk Low risk
Table 8. Risk of bias assessment of included studies
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